New research Illuminates Mechanisms Behind GLP-1 Weight Loss Drugs, Potential for Side Effect Reduction
Recent research presented at a scientific conference is shedding light on how GLP-1 receptor agonists like tirzepatide (Mounjaro®) induce weight loss, and crucially, pinpointing teh brain regions responsible for both their beneficial effects and common side effects like nausea. These studies, utilizing animal models and genetically engineered mice, are exploring avenues to maximize efficacy while minimizing discomfort for individuals using these medications for obesity and type 2 diabetes.
One study investigated a potential strategy to reduce the unpleasant gastrointestinal side effects frequently enough associated with GLP-1 agonists. Researchers found that combining low doses of tirzepatide with oxytocin, a hormone known to promote weight loss without causing nausea, resulted in a significantly greater reduction in bodyweight in obese rats – 11% compared to 6-7% with either treatment alone. Importantly, this enhanced weight loss was achieved without an increase in kaolin intake, a marker of nausea in animals, suggesting the combination successfully mitigated gastrointestinal distress.
Further inquiry focused on where in the brain GLP-1 agonists exert their effects. while itS known these drugs act within the brain to reduce hunger, researchers sought to understand the link between weight loss and nausea. They compared the effects of directly targeting the nucleus tractus solitarius (NTS), a region involved in satiety, versus the area postrema, the brain’s “vomit center.” Surprisingly, activating GLP-1 receptors in the NTS did not lead to weight loss. However, targeting the area postrema resulted in both weight loss and nausea, indicating this region is central to both the desired and undesired effects of these medications.
Another study delved into the neural pathways responsible for appetite suppression. Researchers using genetically engineered mice discovered that GLP-1 drugs influence brain circuits regulating both hunger and cravings for highly palatable, “rewarding” foods. Specifically, activating GLP-1 receptor-expressing cells in the central amygdala lowered food intake by sending signals to the ventral tegmental area, a region crucial for dopamine responses to rewarding stimuli. This activation afterward lowered dopamine activity, revealing a circuit connecting the amygdala, brainstem, and midbrain that appears to play a role in pleasure-based eating and related behaviors.
research explored the often-overlooked effect of GLP-1 agonists on thirst. Observing Brattleboro rats, a strain sensitive to thirst suppression, researchers found meaningful changes in GLP-1 receptor expression in brain regions involved in thirst – the nucleus of the solitary tract and the median preoptic area – after rehydration. This provides insight into the mechanisms behind the thirst-reducing effects of these drugs and could inform the advancement of future medications that maintain metabolic benefits without disrupting hydration.
